There are several metabolic disorders of human and animal metabolism, e.g., hyperglycemia, impaired glucose tolerance, hyperinsulinemia and insulin insensitivity, hyperamylinemia, excess adiposity, and hyperlipidemia. Some or all of the above disorders may occur in the following disease states: non-insulin dependent diabetes mellitus (NIDDM), obesity, hypertension and atherosclerosis.
Hyperglycemia is a condition where the blood glucose level is above the normal level in the fasting state, following ingestion of a meal, or during a provocative diagnostic procedure, e.g., a glucose tolerance test. It can occur in NIDDM as well as obesity. Hyperglycemia can occur without a diagnosis of NIDDM. This condition is called impaired glucose tolerance or prediabetes. Impaired glucose tolerance occurs when the rate of metabolic clearance of glucose from the blood is less than that commonly occurring in the general population after a standard dose of glucose has been orally or parentally administered. It can occur in NIDDM as well as obesity, pre-diabetes and gestational diabetes.
Hyperinsulinemia is defined as having a blood insulin level that is above normal level in the fasting state, following ingestion of a meal or during a provocative diagnostic procedure. It can be seen in NIDDM or obesity and can be associated with or causal in hypertension or atherosclerosis. Hyperinsulinemia can occur without a diagnosis of diabetes. It may occur prior to the onset of NIDDM. Insulin insensitivity, also called insulin resistance, occurs when the insulin-dependent glucose clearance rate is less than that commonly occurring in the general population during diagnostic procedures such as a hyperinsulinemic clamp [See, e.g., DeFronzo, R. A. et al., Am. J. Physiol. 232:E214-E233, (1979)] or a minimal model test. See, e.g., Bergman, R. N. et al., J. Clin. Invest. 68:1456-1467 (1981). Insulin insensitivity is considered also to occur when the blood glucose concentration is higher than that commonly occurring in the general population after intravenous administration of insulin (insulin tolerance test) or when the ratio of serum insulin-to-glucose concentrate is higher than that commonly occurring in the general population after a 10-16 hour fast. Insulin insensitivity may be found in NIDDM or obesity and can also be associated with or causal to hypertension or atherosclerosis.
Hyperamylinemia is defined as having an abnormally high blood amylin level. Amylin is also known as diabetes associated peptide (DAP) and insulinoma associated polypeptide (IAP). Hyperamylinemia can be seen in NIDDM or obesity.
Excess adiposity can be seen in NIDDM associated with obesity as well as obesity without NIDDM. It is defined as a higher fat body mass-to-lean body mass ratio than the commonly occurring in the general population as measured by whole body specific gravity or other generally accepted means.
Hyperlipidemia is defined as having an abnormal level of lipids in the blood. Hyperlipidemia exists when the serum concentration of total cholesterol or total triglycerides or the serum concentration of LDL-cholesterol/HDL-cholesterol is higher than that commonly occurring in the general population. It can be seen in NIDDM or atherosclerosis.
The above disease states could be treated by either ameliorating or preventing the metabolic and biochemical disorders. In addition, humans and animals, which have not been diagnosed as having one of the above disease states but evidencing some or all of the disorders described above, could be benefitted by preventing the development of a currently recognized disease state. Therefore, a compound that is useful in the treatment of hyperglycemia, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, hyperamylinemia, excess adiposity or hyperlipidemia could also be used to treat or prevent NIDDM, obesity, hypertension or atherosclerosis.
3-Guanidinopropionic acid (3-GPA) is an endogenous metabolite found in animals and humans. See, e.g., Hiraga, Y. et al., J. Chromatography 342:269-275 (1985) and Watanabe, Y. et al., Guanidines, edited by Mori et al., Plenum, New York, pp. 49-58 (1983). The compound, which is available from Sigma Chemical Co., has been used extensively in the study of creatine metabolism [See, e.g., Walker, J. B., Adv. Enzymol. 50:177-242 (1979)] and gamma-aminobutyric acid receptor function. See, e.g., Bowery, R. et al., Br. J. Pharmacol. 50:205-218 (1974). Except as noted below, these studies do not relate to 3-GPA's utility in treating human or animal disease.
Guanidine, monoguanidine and diguanidine compounds have been shown to produce hypoglycemia. See, e.g., Watanabe, C., J. Biol. Chem. 33:253-265 (1918); Bischoff, F. et al., Guanidine structure and hypoglycemia 81:325-349 (1929). However, these compounds were observed to be toxic. In 1957, biguanide derivatives, e.g. phenformin and metformin, were used clinically as anti-diabetic agents. Some members of this class continue to be used today while others have been withdrawn from the market or banned in the United States and most Western countries. See, e.g., Schafer, G., Diabete Metabol. (Paris) 9:148-163 (1983).
Gamma-guanidinobutyramide also known as Tyformin, and the HCl salt of Tyformin, known as Augmentin, were investigated as potential anti-diabetic agents from the mid-1960's until the mid-1970's. While Augmentin produced hypoglycemia, it was reported to produce hypertension in dogs [See, e.g., Malaisse, W. et al., Horm. Metab. Res. 1:258-265 (1969)] and respiratory and circulatory collapse in rats and rabbits. See, e.g., Buckle, A. et al., Horm. Metab. Res. 3:76-81 (1971). The free acid of the amide was said to lack hypoglycemic activity [See, e.g., Beeson, M. Et al., Horm. Metab. Res. 3:188-192 (1971)].
British patent 1,153,424 discloses the use of certain esters and amides of guanidino-aliphatic acids in the treatment of diabetes mellitus where hyperuremia is present. The patent does not disclose that these compounds have an effect on hyperglycemia or any other symptom or pathological state related to diabetes. In a Canadian patent, 891509, the use of esters and amides of guanidinoaliphatic acids were disclosed for treating hyperuremia and hyperglycemia in diabetes mellitus. As noted above, the biologic activity of a guanidino alkanoic acid was known to be different and less favorable so as to be ineffective compared to its amide for treating hyperglycemia.
British patent, 1,195,199 discloses the use of guanidino alkanoic acids or their amides or esters in an insulin-containing, parenterally-administered composition for the treatment of hyperglycemia occurring in diabetes. According to this patent, the combining of a guanidino alkanoic acid, amide or ester with insulin reduces the risk of hypoglycemia as compared to insulin alone. British patent 1,195,200 discloses the use of guanidino alkanoic acids in a composition containing a guanidino alkanoic acid amide or ester derivative for the treatment of hyperglycemia occurring in diabetes. In a subsequent British patent, 1,552,179, the use of guanidino alkanoic acids, their salts, amides or esters in combination with a gluconeogensis inhibitor for treating hyperglycemic conditions was disclosed. Metformin was cited as an inhibitor of gluconeogenesis. Biological data indicated the HL 523, the preferred guanidino alkanoic acid derivative, was inactive as a single agent in six of seven experiments where blood glucose concentration was measured in alloxan diabetic mice and only weakly active in the seventh study. Most notably, British patents 1,195,199, 1,195,200 and 1,552,179 do not claim utility for guanidino alkanoic acids, as the sole active component, in compositions for treating hyperglycemic symptoms in diabetes. Among the guanidino alkanoic acids tested, several were inactive as a single agent. Thus, a variety of guanidino alkanolic acids lack significant anti-diabetic activity and combination of these compounds with an agent of known anti-diabetic activity, e.g., metformin, is necessary to show beneficial activity.
Aynsley-Green and Alberti injected rats intravenously with 3-GPA, arginine, guanidine, 4-guanidinobutyramide, and 4-guanidinobutyric acid. Arginine and 3-GPA stimulated insulin secretion transiently, but did not affect the blood glucose concentration while the other compounds stimulated insulin secretion but produced a rise in blood glucose concentration. See, e.g. Aynsley-Green A. et al., Horm. Metab. Res. 6:115-120 (1974). Blachier, et al., observed that 10 mM 3-GPA stimulated insulin secretion by isolated rat islets in vitro. See, e.g., Blachier, F. et al., Endocrinology 124:134-141 (1989). The insulin response induced by 3-GPA was 55% of that occurring when arginine was tested at the same concentration. In rats fed a diet supplemented with 10 mg/g 3-GPA for 30-60 days, the heart glycogen content was increased. See, e.g., Roberts, J. et al., Am. J. Physiol. 243:H911-H916 (1982). Similarly, skeletal muscle glycogen content was increased in rats fed chow supplemented with 10 mg/g of 3-GPA for 6-10 weeks. Mice fed a diet supplemented with 3-GPA at 20 mg/g and supplied with drinking was containing 5 mg/ml 3-GPA for 7-12 weeks had serum glucose concentrations that did not differ significantly from mice receiving unsupplemented chow and water. See, e.g., Moerland, T. et al., Am. J. Physiol. 257:C810-C816 (1989).
With respect to adiposity, it is known that in some, but not all cases [See, e.g., Shoubridge, E. et al., Biochem. J. 232:125-131 (1985)], supplementation of the diet with 10-20 mg/g 3-GPA results in decreased body weight. See, e.g., Moerland, supra and Mahanna, D. et. al., Exper. Neurol. 68:114-121 (1980). This effect has been attributed to decreased skeletal muscle mass and has not been attributed to reduced adiposity or decreased lipid storage. See, e.g., Mahanna, supra; Shields, R. et al., Lab. Invest. 33:151-158 (1975); and Otten et al.: Thyrotoxic Myopathy in Mice: Accentuation by a Creatine Transport Inhibitor. Metabolism Vol. 35, No. 6, (pages 481-484, 1986).
Patients suffering from any of the above metabolic disorders often experience lack of stamina and endurance and decreased exercise capacity. Other diseases that may result in decreased exercise ability include: diseases resulting from muscular dysfunction, such as post-poliomyelitis chronic muscle fatigue syndrome or muscular dystrophy; diseases resulting from chronic muscular weakness associated with advanced age or chronic immobilization; diseases resulting from tissue hypoxia, such as peripheral claudication; angina; myocardial infarction; and stroke.
What is needed in the art is a therapy that increases endurance, stamina and exercise capacity in patients who are performing at less that optimal levels.